Recently, a chemical delivery system (CDS) has been devised which promises to deliver centrally acting drugs to the brain in a site-specific and sustained manner. In accord with this system, the desired central effects of drugs can be achieved without the high concentrations throughout the body which are believed to be responsible for the significant toxic effects typically associated with the drugs. Moreover, this system allows delivery to the brain of drugs which are not themselves capable of passing the blood-brain barrier (BBB).
The drug delivery system referred to above and its applicability to .gamma.-aminobutyric acid (GABA) is generally described in Bodor U.S. Pat. No. 4,479,932 issued to UNIVERSITY OF FLORIDA on Oct. 30, 1984, and more specifically in UNIVERSITY OF FLORIDA's International Application No. PCT/US83/00725 (published under International Publication No. WO 83/03968), in Bodor U.S. Pat. No. 4,540,564 issued to UNIVERSITY OF FLORIDA on Sept. 10, 1985, and in copending Bodor U.S. patent application Ser. No. 665,940, filed Oct. 29, 1984. Briefly, according to the GABA-CDS system, the target drug is tethered to a reduced, blood-brain barrier penetrating lipoidal form of a dihydropyridine.revreaction.pyridinium salt type redox carrier. Oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt type carrier/GABA entity prevents elimination thereof from the brain, while elimination from the general circulation is accelerated, and subsequent cleavage of the quaternary carrier/GABA species results in sustained delivery of GABA in the brain and facile elimination of the carrier moity.
In a representative embodiment of the GABA-CDS system, the carboxyl function of GABA is suitably protected to prevent premature metabolism while the trigonelline-type carrier is linked to the drug through GABA's amino function. See in particular the aforementioned U.S. Pat. Nos. 4,479,932, at column 14, line 45 to column 18, line 30; and 4,540,564, at column 37, line 60 to column 41, line 34 and again at column 55, line 1 to column 61; and especially the aforementioned copending U.S. application Ser. No. 665,940, Examples 96-103, which detail preparation of 1-methyl-3{N-[(3'-benzyloxycarbonyl)propyl]}carbamoyl-1,4-dihydropyridine and 1-methyl-3{N-[(3'-cyclohexyloxycarbonyl)propyl]}carbamoyl-1,4-dihydropyrid ine and intermediates thereto.
As discussed at length in the aforementioned U.S. patents and patent application, the rational of the GAPA/carrier approach derives from the GABA hypothesis of epilepsy. It has been shown that GABA neuron function is impaired in at least certain types of human epilepsy, while animal studies have shown that seizures are induced by reduction of GABA neuron function to a critical degree by (1) inhibition of GABA synthesis, (2) blockade of GABA receptors or (3) inhibition of GABA-receptor mediated ionic events. In addition, enhancement of GABA synaptic activity (by direct receptor stimulation or by increasing GABA levels in the synapse) has a potent and wide spectrum anticonvulsant effect. However, GABA itself, when systemically administered, does not penetrate the normal blood-brain barrier to any significant extent. The GABA-CDS is thus proposed by the aforementioned patent publications as one means of providing for the effective, selective and non-toxic treatment of epilepsy, but no other potential uses of any of the GABA/carrier compounds are disclosed or suggested therein.
Anxiety is a psychological state characterized by apprehension, nervousness, restlessness and the feeling of insecurity about one's future. While anxiety is a well-defined psychological condition, it is extremely difficult to evaluate objectively, particularly since anxiety is a component of several neuroses and psychoses. Additionally, anxiety varies in its intensity. Mild anxiety is described as restlessness, nervousness, uneasiness or anxiousness. More intense anxiety expresses itself as agitation, anxiety attacks, panic attacks or anxiety neurosis. Severe anxiety is a component of neurocirculatory asthenia, hysterical neurosis, hypochondriacal neurosis, obsessive-compulsive neurosis, phobic neurosis and neuroasthenic neurosis.
Anxiety is an integral part of the human response to external conditions. Mild anxiety is often associated with the stress of everyday living and the cause of the anxiety is not well-defined. By contrast, a more severe anxiety is caused by defined life events, i.e. a prospective surgical or medical procedure, marriage, divorce, the death of a family member or friend or the like. In such cases, the anxiety usually wanes as time passes.
Medical conditions and drug use can also cause anxiety. Anxiety is associated with hyperthyroidism and hypercorticosteroidism, as well as with the therapeutic administration of thyroid hormones and glucocorticoids. The changing gonadal steroid environment which causes premenstrual syndrome, post-partum depression and post-menopausal mood changes is frequently associated with anxiety. Anxiety results from the therapeutic use of the .beta.-adrenergic agonist isoproterenol, and the .alpha..sub.2 -adrenergic antagonists, piperoxane and yohimbine. The use of cocaine and amphetamines or their derivatives causes anxiety and the use of tetrahydrocannabinols causes anxiety, particularly among first-time users. Finally, anxiety is a consistent occurrence in patients experiencing withdrawal from addictive drugs such as nicotine, alcohol, benzodiazepines, barbiturates, opiates, cocaine, tetrahydrocannabinols and their derivatives. Anxiety increases with the intensity of the withdrawal.
Most drugs which are used in the treatment of anxiety are either sedatives or exhibit sedating properties. Even the benzodiazepines, which not only have anticonvulsant/antiepileptic utility but also are the most-widely prescribed anxiolytics, suffer from sedating side effects. Diazepam, for example, produces antianxiety effects at blood concentrations of 400-600 ng/ml, but sedative effects and psychomotor impairment are observed beginning at 300-400 ng/ml. See Goodman and Gilman's The Pharmacological Basis of Therapeutics, sixth edition, ed. A. G. Gilman et al, Macmillan Publishing Co., Inc., New York, 1980, Chapter 19, pp. 436-447.
For many years, little was known about the mechanism of action of the benzodiazepines. However, a large body of evidence now supports the belief that the neurochemical and neuropharmacological actions of the benzodiazepines, including their anxiolytic and sedative effects, may result from their enhancement of GABA-mediated transmission. Benzodiazepines are now thought to increase the affinity of GABA receptors for GABA and to thus facilitate GABAergic transmission. The discovery of this relationship between the benzodiazepines and GABA, and similar discoveries relating to the barbiturates and other GABAergic agents, as well as research on anxiogenic drugs, suggest that the neurotransmitter GABA in involved in the etiology of anxiety. Nevertheless, the hypothesized involvement of GABA in anxiety is controversial. For representative literature in this area, see: D.J. Sanger et al, in L.E.R.S. Volume 4, ed. G. Bartholini et al, Raven Press, New York, 1986, pp. 77-84; M. G. Corda et al, in GABAergic Transmission and Anxiety. ed. G. Biggio et al, Raven Press, New York, 1986, pp. 121-136; J.-Y. Wu et al, in GABAergic Transmission and Anxiety, ed. G. Biggio et al, Raven Press, New York, 1986, pp. 161-176; C. Martini et al, in GABAergic Transmission and Anxiety, ed. G. Biggio et al, Raven Press, New York, 1986, pp. 1-10; G. Bartholini et al, in L.E.R.S. Volume 3, ed. G. Bartholini et al, Raven Press, New York, 1985, pp. 1-30; D. N. Stephens et al, in GABAergic Transmission and Anxiety, ed. G. Biggio et al, Raven Press, New York, 1986, pp. 91-106; and R. W. Olsen et al, in GABAergic Transmission and Anxiety, ed. G. Biggio et al, Raven Press, New York, 1986, pp. 21-32. (The expression "L.E.R.S." used herein is a recognized abbreviation for Laboratories d'Etudes et de Recherches Synthelabo, Paris, France. Volume 3 of the L.E.R.S. monograph series referred to herein is entitled Epilepsy and GABA Receptor Agonists: Basic and Therapeutic Research, while Volume 4 is entitled GABA and Mood Disorders: Experimental and Clinical Research The book GABAergic Transmission and Anxiety referred to herein is Volume 41 of the Advances in Biochemical Psychopharmacology series.)
Recently, a group of specific GABA receptor agonists has been developed which appears to offer a wide range of therapeutic actions. This group of benzylidene-type GABA receptor agonists includes progabide and fengabine. These compounds have been tested for a number of therapeutic applications in a variety of animal and clinical test situations reported in the literature.
Fengabine has been shown to be active in animal models predicting human antidepressant activity. In clinical trials assessing fengabine's effects on depression, somewhat conflicting results on its effects on anxiety have also been reported. T. Lemperiere et al, in L.E.R.S. Volume 4, ed. G. Bartholini et al, Raven Press, New York, 1986, pp. 161-162, report that, in a group of ten patients, the Hamilton Rating Scale for Anxiety (HRSA) mean total score decreased, indicating that fengabine was not anxiogenic. M. Toscano Aguilar et al, in L.E.R.S. Volume 4, ed. G. Bartholini et al, Raven Press, New York, 1986, pp. 167-168, report a lower total score on theHamilton anxiety rating scale in a group of ten patients. On the other hand, R. Volmat et al, in L.E.R.S. Volume 4, ed. G. Bartholini et al, Raven Press, New York, 1986, pp. 169-170, indicate that two patients out of eight dropped out of the study because of the appearance of an anxiety state.
The reports are also conflicting as regards progabide, progabide having been found to be active in some anxiolytic tests and inactive in others. Thus, G. Bartholini et al, in L.E.R.S. Volume 3, ed. G. Bartholini et al, Raven Press, New York, 1985, pp. 1-30, state that diazepam and progabide have both been reported to decrease the escape response which is induced by electrical stimulation of periaqueductal gray matter, but that clinical trials have shown minimal anxiolytic properties. In related animal studies, F. G. Graeff et al, in L.E.R.S. Volume 4, ed. G. Bartholini et al, Raven Press, New York, 1986, p. 101, report that microinjection of progabide, benzodiazepines and other GABAergics into the dorsal periaqueductal gray matter (DPAG) in rats whose DPAG is electrically stimulated similarly increase the threshold of stimulation-induced flight. Muscimol, another GABA agonist, has been reported to exhibit anticonvulsant and anxiolytic action, but also causes severe sedation; A. Guidotti et al, in L.E.R.S. Volume 3, ed. G. Bartholini et al, Raven Press, New York, 1985, pp. 31-41. However, G. Bartholini, in L.E.R.S. Volume 4, Raven Press, New York, 1986, pp. 1-7, states that, contrary to what might be expected from animal tests, in clinical studies anxiety states have not been improved by administration of muscimol or progabide; clinical anticonvulsant studies of progabide, in contrast, correlate well with earlier findings of anticonvulsant activity in animals as well as lack of sedating side effects.
A possible explanation for the conflicting reports on progabide's activity in anxiolytic testing is offered by D. J. Sanger et al, in L.E.R.S. Volume 4, ed. G. Bartholini et al, Raven Press, New York, 1986, pp. 77-84. Those authors report that in an aversive brain stimulation study, progabide and diazepam gave similar results, supporting other findings of an anxiolytic response in tests involving electrical stimulation of periaqueductal gray matter. But the authors also report several other behavioral tests in which progabide gave results unlike the benzodiazepines and other anxiolytics. For example, in electroshock punishment procedures in which thirsty rats are shocked for drinking from a water tube, benzodiazepines attenuate the results and this effect is considered predictive of clinical anti-anxiety activity. Progabide, on the other hand, does not give results significantly different from control animals. It would appear that progabide's clinical lack of impressive anxiolytic effects correlates well with the punishment test but not with the tests involving aversive electrical stimulation of periaqueductal gray matter.
GABA itself has been recently reported to act in a similar manner to certain GABA receptor agonists in aversive brain stimulation studies when the drug is injected directly into selected brain regions. Thus, F. G. Graeff et al, in L.E.R.S. Volume 4, ed. G. Bartholini et al, Raven Press, New York, 1986, p. 101, report that in rats electrically stimulated at the dorsal periaqueductal gray matter (DPAG), microinjection into the DPAG of the benzodiazepines chlordiazepoxide and midazolam, of GABA, of progabide and of the barbiturate pentobarbital all result in an increase of the threshold of stimulation-induced flight. G. Bartholini et al, in L.E.R.S. Volume 3, ed. G. Bartholini et al, Raven Press, New York, 1985, pp. 1-30, had earlier referred to the finding that ". . . GABA itself injected into the periaqueductal gray matter or the midbrain raphe exhibits an anxiolytic action in aversive situations . . . both progabide and diazepam decrease the escape response induced by electrical stimulation of the periaqueductal gray matter . . . "